Leveraging biomarkers and translational medicine for preclinical safety - Lessons for advancing the validation of alternatives to animal testing.

This article explores the potential of principles established in translational medicine for the use of bio-markers to advance the validation of alternatives to animal testing in preclinical safety assessment. It examines especially how such principles can enhance the predictive power, mechanistic under-standing, and human relevance of new approach methodologies (NAMs). Key concepts from translational medicine, such as fit-for-purpose validation, evidence-based approaches, and inte-grated testing strategies, are already being applied to the development and validation of NAMs.

Dietary Sugar and Saturated Fat Consumption Associated with the Gastrointestinal Microbiome during Pregnancy.

Background: Growing evidence supports changes in the gastrointestinal microbiome over the course of pregnancy may have an impact on the short- and long-term health of both the mother and the child.

Objective: Our objective was to explore the association of diet quality, as measured by the Healthy Eating Index (HEI), with the composition and gene ontology (GO) representation of microbial function in the maternal gastrointestinal microbiome during pregnancy.

Methods: We conducted a retrospective, observational analysis of n = 185 pregnant participants in the Pregnancy Eating Attributes Study.

Overexpression of soluble epoxide hydrolase reduces post-ischemic recovery of cardiac contractile function.

Cytochromes P450 can metabolize endogenous fatty acids, such as arachidonic acid, to bioactive lipids such as epoxyeicosatrienoic acids (EETs) that have beneficial effects. EETs protect hearts against ischemic damage, heart failure or fibrosis; however, their effects are limited by hydrolysis to less active dihydroxy oxylipins by soluble epoxide hydrolase (sEH), encoded by the epoxide hydrolase 2 gene (EPHX2, EC 3.3.

Disruption of Ephx2 in cardiomyocytes but not endothelial cells improves functional recovery after ischemia-reperfusion in isolated mouse hearts.

Cytochromes P450 metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs) which have numerous effects. After cardiac ischemia, EET-induced coronary vasodilation increases delivery of oxygen/nutrients to the myocardium, and EET-induced signaling protects cardiomyocytes against postischemic mitochondrial damage. Soluble epoxide hydrolase 2 (EPHX2) diminishes the benefits of EETs through hydrolysis to less active dihydroxyeicosatrienoic acids.

Cardiac Development in the Presence of Cadmium: An Study Using Human Embryonic Stem Cells and Cardiac Organoids.

Background: Exposure to cadmium (Cd) is associated with cardiovascular diseases. Maternal Cd exposure is a significant risk factor for congenital heart disease. However, mechanisms of Cd on developmental cardiotoxicity are not well defined.

Comparison of National Vulnerability Indices Used by the Centers for Disease Control and Prevention for the COVID-19 Response.

Objective: Vulnerability indices use quantitative indicators and geospatial data to examine the level of vulnerability to morbidity in a community. The Centers for Disease Control and Prevention (CDC) uses 3 indices for the COVID-19 response: the CDC Social Vulnerability Index (CDC-SVI), the US COVID-19 Community Vulnerability Index (CCVI), and the Pandemic Vulnerability Index (PVI). The objective of this review was to describe these tools and explain the similarities and differences between them.

Life Course Racism and Depressive Symptoms among Young Black Women.

The objective of this study is to evaluate the life course effects of racism on depressive symptoms in young Black women and to identify particularly sensitive periods. Guided by life-course theory and using logistic regression, we analyzed baseline data on racism frequency and stress from racism at two time periods (before age 20 and during the 20s) and follow-up data (at approximate 20-month intervals) on depressive symptoms (using a modified 11-item Center for Epidemiologic Studies Depression Scale, CES-D) among 1612 Black women participants aged 23-34 years living in Detroit, MI. Of the 1612 women, 65% reported experiencing some racism at baseline, and 36.

Toward an Integrated System of Climate Change and Human Health Indicators: A Conceptual Framework.

Environmental health indicators are helpful for tracking and communicating complex health trends, informing science and policy decisions, and evaluating public health actions. When provided on a national scale, they can help inform the general public, policy makers, and public health professionals about important trends in exposures and how well public health systems are preventing those exposures from causing adverse health outcomes. There is a growing need to understand national trends in exposures and health outcomes associated with climate change and the effectiveness of climate adaptation strategies for health.

Intake of Lycopene and other Carotenoids and Incidence of Uterine Leiomyomata: A Prospective Ultrasound Study.

Background: Uterine leiomyomata (UL) are the leading indication for hysterectomy in the United States. Dietary supplementation with lycopene was associated with reduced size and incidence of oviduct leiomyoma in the Japanese quail. Two US prospective cohort studies of women reported little association between intake of lycopene, or other carotenoids, and UL incidence.

Organs-on-chips: into the next decade.

Organs-on-chips (OoCs), also known as microphysiological systems or 'tissue chips' (the terms are synonymous), have attracted substantial interest in recent years owing to their potential to be informative at multiple stages of the drug discovery and development process. These innovative devices could provide insights into normal human organ function and disease pathophysiology, as well as more accurately predict the safety and efficacy of investigational drugs in humans. Therefore, they are likely to become useful additions to traditional preclinical cell culture methods and in vivo animal studies in the near term, and in some cases replacements for them in the longer term.

The clearance of dead cells by efferocytosis.

Multiple modes of cell death have been identified, each with a unique function and each induced in a setting-dependent manner. As billions of cells die during mammalian embryogenesis and daily in adult organisms, clearing dead cells and associated cellular debris is important in physiology. In this Review, we present an overview of the phagocytosis of dead and dying cells, a process known as efferocytosis.

Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis.

Aims: Cardiovascular side effects caused by non-steroidal anti-inflammatory drugs (NSAIDs), which all inhibit cyclooxygenase (COX)-2, have prevented development of new drugs that target prostaglandins to treat inflammation and cancer. Microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors have efficacy in the NSAID arena but their cardiovascular safety is not known. Our previous work identified asymmetric dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase, as a potential biomarker of cardiovascular toxicity associated with blockade of COX-2.

At the Interface of Lifestyle, Behavior, and Circadian Rhythms: Metabolic Implications.

Nutrient metabolism is under circadian regulation. Disruption of circadian rhythms by lifestyle and behavioral choices such as work schedules, eating patterns, and social jetlag, seriously impacts metabolic homeostasis. Metabolic dysfunction due to chronic misalignment of an organism's endogenous rhythms is detrimental to health, increasing the risk of obesity, metabolic and cardiovascular disease, diabetes, and cancer.

Stewardship of research resources.

Most accounts of research ethics focus on the importance of a handful of ethical and epistemological norms for the conduct of science, such as honesty, integrity, transparency, accountability, objectivity, collegiality, fairness, social responsibility, but have little to say about another, less well-known norm that also deserves attention: stewardship of research resources. Many of the behaviors and practices that are widely regarded as unethical or ethically questionable involve wasting or misusing money, time, and other resources. While good stewardship of resources may not be as crucial to the ethics of science as other norms, it is an important consideration that scientists should keep in mind when managing their own resources or mentoring students and trainees in the responsible conduct of research.

Maternal levels of perfluoroalkyl substances (PFASs) during pregnancy and childhood allergy and asthma related outcomes and infections in the Norwegian Mother and Child (MoBa) cohort.

Introduction: Prenatal exposure to perfluoroalkyl substances (PFASs) has been inconsistently associated with asthma and allergic diseases and increased number of infections in early childhood. We examined the association of PFASs measured in pregnancy with childhood asthma, allergies and common infectious diseases in a prospective pregnancy cohort followed to age 7 years.

Material And Methods: Six PFASs (out of 19 measured) with at least 80% of measurements above the limit of quantification (LOQ) in maternal plasma during pregnancy in two subcohorts of the Norwegian Mother and Child Cohort Study (MoBa) were analyzed in relation to health outcomes: perfluorooctane sulfonic acid (PFOS), acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluoroundecanoic acid (PFUnDA), and perfluoroheptane sulfonic acid (PFHpS).

A statistical method for joint estimation of cis-eQTLs and parent-of-origin effects under family trio design.

RNA sequencing allows one to study allelic imbalance of gene expression, which may be due to genetic factors or genomic imprinting (i.e., higher expression of maternal or paternal allele).

Beyond the RfD: Broad Application of a Probabilistic Approach to Improve Chemical Dose-Response Assessments for Noncancer Effects.

Background: The National Academies recommended risk assessments redefine the traditional noncancer Reference Dose (RfD) as a probabilistically derived risk-specific dose, a framework for which was recently developed by the World Health Organization (WHO).

Objectives: Our aim was to assess the feasibility and implications of replacing traditional RfDs with probabilistic estimates of the human dose associated with an effect magnitude M and population incidence I (HDI).

Methods: We created a comprehensive, curated database of RfDs derived from animal data and developed a standardized, automated, web-accessible probabilistic dose-response workflow implementing the WHO framework.

Household fuel use and biomarkers of inflammation and respiratory illness among rural South African Women.

Though literature suggests a positive association between use of biomass fuel for cooking and inflammation, few studies among women in rural South Africa exist. We included 415 women from the South African Study of Women and Babies (SOWB), recruited from 2010 to 2011. We obtained demographics, general medical history and usual source of cooking fuel (wood, electricity) via baseline questionnaire.

Menstrual cycle characteristics as determinants of plasma concentrations of perfluoroalkyl substances (PFASs) in the Norwegian Mother and Child Cohort (MoBa study).

Introduction: Perfluoroalkyl substances (PFASs) are fluorinated organic compounds that have been used in a variety of industrial and consumer applications. Menstruation is implicated as a possible route of elimination for PFASs in women. The overall purpose of this study was to examine menstrual cycle characteristics as determinants of plasma PFAS concentrations in women.

Kidney Transplantation in a Patient Lacking Cytosolic Phospholipase A Proves Renal Origins of Urinary PGI-M and TX-M.

Rationale: The balance between vascular prostacyclin, which is antithrombotic, and platelet thromboxane A, which is prothrombotic, is fundamental to cardiovascular health. Prostacyclin and thromboxane A are formed after the concerted actions of cPLAα (cytosolic phospholipase A) and COX (cyclooxygenase). Urinary 2,3-dinor-6-keto-PGF (PGI-M) and 11-dehydro-TXB (TX-M) have been taken as biomarkers of prostacyclin and thromboxane A formation within the circulation and used to explain COX biology and patient phenotypes, despite concerns that urinary PGI-M and TX-M originate in the kidney.

Oral contraceptive use as a determinant of plasma concentrations of perfluoroalkyl substances among women in the Norwegian Mother and Child Cohort (MoBa) study.

Objective: Because oral contraceptives (OC) tends to lessen menstrual fluid loss - a route of excretion for perfluoroalkyl substances (PFASs) - we hypothesized that such use would be positively associated with PFAS concentrations.

Methods: This analysis was based on the Norwegian Mother and Child Cohort (MoBa) study. We included 1090 women from two previous substudies of women enrolled from 2003 to 2007.